A new mathematical approach for qualitative modeling of the insulin-TOR-MAPK network

Abstract

In this paper we develop a novel mathematical model of the insulin-TOR-MAPK signaling network that controls growth. Most data on the properties of the insulin and MAPK signaling networks are static and the responses to experimental interventions, such as knockouts, overexpression, and hormonal input are typically reported as scaled quantities. The modeling paradigm we develop here uses scaled variables and is ideally suited to simulate systems in which much of the available data are scaled. Our mathematical representation of signaling networks provides a way to reconcile theory and experiments, thus leading to a better understanding of the properties and function of these signaling networks. We test the performance of the model against a broad diversity of experimental data. The model correctly reproduces experimental insulin dose-response relationships. We study the interaction between insulin and MAPK signaling in the control of protein synthesis, and the interactions between amino acids, insulin and TOR signaling. We study the effects of variation in FOXO expression on protein synthesis and glucose transport capacity, and show that a FOXO knockout can partially rescue protein synthesis capacity of an insulin receptor (INR) knockout. We conclude that the modeling paradigm we develop provides a simple tool to investigate the qualitative properties of signaling networks.

Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?

“…mTOR is not only activated by nitrogen substrates, provided by digestion of macronutrients, but also by various stimuli, such as growth factors and energy stress. For these reasons, mTOR is at the center of a complex network that controls protein synthesis, cell differentiation, growth and proliferation [31][32][33]. However, other evidence suggest that mTOR may also play a positive role in cancer patients.…”

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

“…Aldridge et al [140] have studied insulin and EGF, but also tumor necrosis factor (TNF), involved in inflammation, and focus on the crosstalk between these signaling pathways. Recently, a pure theoretical attempt at modeling the complete insulin signaling network, including ERK, was published [141]. None of these models were based on dynamic data from human adipocytes, and we could not use them in the development of the extended insulin signaling model in Paper IV.…”

“…The authors have formulated simple equations for a sigmoidal activation to simulate dose-response behaviors and compare with data from different sources. Again, in [141] the lack of dynamic data is a limitation of the study. In contrast, a modeling approach of the insulin signaling network in HeLa and C2C12 cell lines has used dynamic data for many signaling intermediaries [59].…”

“…Despite all available models of ERK signaling, there are only a few mathematical models for insulin control of the ERK signaling pathway [96,140,141]. Borisov et al [96] have studied interactions between insulin-and EGF-stimulated ERK signaling.…”

“…Despite the shortcomings of the Sedaghat model, it has been extensively used and also further developed [143][144][145] and analyzed [146]. Recently, another more theoretical attempt at constructing a detailed model of insulin signaling was published [141]. The authors have formulated simple equations for a sigmoidal activation to simulate dose-response behaviors and compare with data from different sources.…”